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Cited by 127Parkinson's Disease Mechanisms and TreatmentsGenetic Associations and EpidemiologyNeurological disorders and treatments

Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease

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Liu, Ganqiang, Peng, Jiajie, Liao, Zhixiang, Locascio, Joseph J., Corvol, Jean-Christophe, Zhu, Frank, Dong, Xianjun, Maple-Grødem, Jodi +33 more·2021·Nature Genetics
DOI 10.1038/s41588-021-00847-6PMC PMC8459648
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Abstract

A key driver of patients' well-being and clinical trials for Parkinson's disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 × 10-11), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10-8) and WWOX (HR = 2.12, P = 2.37 × 10-8) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.

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  • The observation of distinct tissue enrichment for MS severity versus susceptibility is unique to MS.

    “Although divergent genetic determinants of susceptibility and progression have been noted in other conditions8,9,36, the observation of distinct tissue enrichment is to our knowledge unique to MS.”

    From Locus for severity implicates CNS resilience in progression of multiple sclerosis (2023) · cites this paper as [9]

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Authors
Liu, G., Peng, J., Liao, Z., Locascio, J. J., Corvol, J.-C., Zhu, F., Dong, X., Maple-Grødem, J., Campbell, M. C., Elbaz, A., Lesage, S., Brice, A., Mangone, G., Growdon, J. H., Hung, A. Y., Schwarzschild, M. A., Hayes, M. T., Wills, A.-M., Herrington, T. M., Ravina, B., Shoulson, I., Taba, P., Kõks, S., Beach, T. G., Cormier-Dequaire, F., Alves, G., Tysnes, O.-B., Perlmutter, J. S., Heutink, P., Amr, S. S., van Hilten, J. J., Kasten, M., Mollenhauer, B., Trenkwalder, C., Klein, C., Barker, R. A., Williams-Gray, C. H., Marinus, J., International Genetics of Parkinson Disease Progression (IGPP) Consortium, van Hilten, J. J., & Scherzer, C. R.
Affiliations
  • Brigham and Women's Hospital (US)
  • Centre National de la Recherche Scientifique (FR)
  • Washington University in St. Louis (US)
  • Inserm (FR)
  • Harvard University (US)
  • Praxis Precision Medicines Inc. (United States) (US)
  • University of Rochester Medicine (US)
  • University of Tartu (EE)
  • Murdoch University (AU)
  • Banner Sun Health Research Institute (US)
  • Stavanger University Hospital (NO)
  • Haukeland University Hospital (NO)
  • German Center for Neurodegenerative Diseases (DE)
  • University Hospital Schleswig-Holstein (DE)
  • Universitätsmedizin Göttingen (DE)
  • Wellcome/MRC Cambridge Stem Cell Institute (GB)
  • Leiden University Medical Center (NL)
Corresponding author
Scherzer, Clemens R.
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2021-05-06
Volume
53
Issue
6
Pages
787-793
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-021-00847-6
PMC
PMC8459648
OpenAlex
W3157584621
Cited by
127
References
6
Citations by year
2026: 12 · 2025: 25 · 2024: 21 · 2023: 25 · 2022: 34 · 2021: 10
FWCI
10.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • Murdoch University Research Portal (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • HAL (submittedVersion)
  • DZNE Pub (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (R01NS115144, U01NS095736, U01NS100603)
  • National Natural Science Foundation of China (31900475)
  • Sun Yat-sen University (19ykpy146)
  • Shenzhen Science and Technology Innovation Commission (JCYJ20190807161601692)
  • Guangdong Science and Technology Department (2019QN01Y139)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Neurology › Neurological disorders and treatments
Keywords
Parkinson's disease, disease progression, dementia, WWOX, glucocerebrosidase, apolipoprotein E, polygenic risk score, genetic architecture, survival analysis, cognitive decline
MeSH terms
Cognition, Cognition Disorders, Glucosylceramidase, Humans, Longitudinal Studies, Mutation, Parkinson Disease, Risk Factors, Synapses, Proportional Hazards Models, Survival Analysis, Disease Progression, Genetic Predisposition to Disease, Multifactorial Inheritance, Apolipoprotein E4, Genome-Wide Association Study, Genetic Loci

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